In IVF, the goal is not simply to use more medication but to recruit the right number of eggs safely and decide the next step from real-time results, a strategy presented by Dr Harry Karpouzis – Founder & Scientific Director of IVF Pelargos Fertility Group in Athens.
In a natural cycle, the ovaries usually develop 1 dominant follicle, with 1 egg inside per month. IVF temporarily changes that pattern by using medication to encourage several follicles to grow during the same cycle. The aim is to create more opportunities for fertilisation and embryo development.
Treatment typically involves injections or tablets for about 8 to 12 days. The medications are intended to accomplish three things: recruit multiple follicles, help them grow at a similar pace, and prevent ovulation before the eggs can be collected.
That last task is crucial. A follicle can potentially ovulate when it reaches 13 to 14 mm, so treatment must prevent the body’s natural LH surge until the clinical team is ready to give the trigger injection. The trigger coordinates final egg maturation and the timing of egg collection.
There is no universally best IVF protocol. The appropriate plan depends on ovarian reserve, age, previous treatment response, follicle count, weight and the goal of treatment—whether that is a first IVF cycle, fertility preservation, embryo banking or genetic testing.
The backbone of most stimulation cycles is a group of medications called gonadotropins. These contain FSH, sometimes combined with LH, or may contain LH alone. FSH is naturally produced by the brain and helps stimulate follicle growth.
Most patients begin stimulation around day 2 to day 3 of the menstrual cycle. Medication doses may then change as ultrasound scans and blood tests show how the ovaries are responding. A starting prescription is not necessarily the final prescription.
A second group of medicines prevents premature ovulation. GnRH antagonist medications, including Cetrotide and Galtron, suppress the LH surge during stimulation. The antagonist is commonly introduced once the follicles are developing, although the daily dose does not always need to continue unchanged.
Blood tests measuring LH and estradiol can help determine whether an antagonist is needed on a particular day. If LH is very low, omitting a dose may be considered because the immediate risk of ovulation is low. On the other hand, if the medication suppresses LH too strongly, it may contribute to a higher proportion of immature eggs, so treatment may need to be adjusted.
Other medicines have more specific roles:
The choice is not simply about which drug is strongest. It is about keeping follicle development coordinated while avoiding premature ovulation, excessive hormone levels and unnecessary medication.
Dose selection is one of the most individualized parts of IVF. When there are enough follicles to respond, higher doses may be used to recruit as many eggs as possible. But in a patient with only three or four follicles, increasing the dose may not produce additional eggs.
For patients with fewer than four follicles, a high-dose approach may add cost without adding benefit. A milder plan using fewer injections can sometimes produce a similar number of eggs. This is the thinking behind mild combination protocols, which pair gonadotropin injections with letrozole or clomiphene and resemble a mini IVF cycle.
These protocols may be useful for some poor ovarian responders, particularly when higher doses are unlikely to recruit more follicles. They can reduce injection requirements and cost, but they also have disadvantages. Follicle growth may be harder to control during the first days, and premature ovulation is possible.
When there are more than four follicles, higher doses may be preferred to maximise recruitment. The initial dose still needs to reflect factors such as age, follicle number, weight and other clinical details. During treatment, the dose can be reduced if hormone levels rise too quickly or adjusted if the response is weaker than expected.
Patients with polycystic ovaries require particular caution because they may respond strongly. In some patients with resistant polycystic ovaries, treatment may begin at a higher dose and then be reduced as the blood tests clarify the response. The important principle is not a fixed dose but ongoing personalisation.
The antagonist protocol is the most commonly used approach and is generally the first protocol to consider. It begins with stimulation early in the cycle, followed by medication to block the LH surge. The plan can then be modified according to follicle growth and hormone results.
The older long protocol, which uses a GnRH agonist for ovarian suppression, is used less often. It takes longer, requires more injections and costs more. It may still have a role in endometriosis, but it has not shown a significant benefit over an antagonist protocol, particularly when embryos are going to be frozen.
The soft flare protocol, which combines an antagonist with an agonist and injections, has also not shown additional benefit compared with other approaches. It may occasionally be considered when previous protocols have failed, and follicle recruitment needs a boost in a poor ovarian responder.
Progesterone-based suppression is another option. It is used in some fertility-preservation and double-stimulation plans, and may be attractive for patients who want to avoid antagonist injections. However, it requires advance planning because a fresh embryo transfer cannot be performed in a progesterone-based cycle. The embryos must be frozen instead, and reports have suggested that some patients may develop fewer quality blastocysts, although the evidence remains mixed.
IVF stimulation is not a prescription that runs on autopilot. Ultrasounds are performed frequently, with blood tests checked at each ultrasound. Estradiol, LH and progesterone provide information about whether follicles are developing together, whether ovulation is approaching and whether the medication doses remain appropriate.
The plan can change substantially after stimulation begins. A dose may be reduced when estradiol becomes very high. LH-containing medication may be added if LH falls too low. An antagonist may be stopped if excessive suppression raises concern about immature eggs.
This monitoring also helps determine the trigger. Options include a GnRH agonist trigger, an hCG trigger such as Ovidrel, or a dual trigger that combines both. The choice and timing depend on the blood tests, follicle number, estrogen level, LH, weight and the treatment objective.
A dual trigger may be considered for poor ovarian responders, older patients or patients who previously had a high proportion of immature eggs. hCG requires caution because it can increase the risk of hyperstimulation, particularly in patients with polycystic ovaries, high AMH, good ovarian reserve or other features associated with a strong response.
When hyperstimulation is a concern, an agonist trigger may be used instead of hCG. A freeze-all strategy can also reduce pressure to transfer an embryo immediately while hormone levels are high. Careful monitoring, dose adjustments and the choice of trigger are central to safety.
A fresh transfer is not automatically the best option. The decision is made after considering progesterone, estrogen, the trigger used, the risk of hyperstimulation and whether PGT-A is planned.
A fresh transfer may be avoided when progesterone is higher than 1.2, when estrogen levels are very high, after an agonist-only trigger or when progesterone has been used to suppress ovulation. It is also avoided when embryos will undergo PGT-A because the embryos need to be frozen while testing is performed.
Frozen transfer is preferred in some patients with adenomyosis or endometriosis. In endometriosis, one approach is to begin with an antagonist protocol, freeze the embryos and then downregulate the ovaries before transfer. Reaching an older age alone does not mean fresh transfer must be abandoned, but the relevant hormone and treatment parameters still need to be suitable.
Modern vitrification has made clinicians less concerned that freezing will harm embryo quality. That flexibility allows the team to focus on obtaining embryos safely and transferring them when the uterine and hormonal environment is considered more appropriate.
Some patients produce only a small number of eggs in a cycle. In these cases, collecting eggs over more than one cycle may increase the total number available for fertilisation and embryo development. This strategy, known as embryo banking, is often considered in poor ovarian reserve and advanced maternal age.
Embryo banking may also be relevant when PGT-A is planned. More embryos provide more material for testing, although banking should be tailored to the patient rather than assumed to be necessary for everyone.
Double stimulation is one way to collect eggs twice during a single menstrual cycle. After the first egg collection, stimulation begins again so that a second collection can be performed without waiting for the next period. The main advantage is time, which can matter in fertility preservation, oncological patients and some patients with poor ovarian reserve.
Double stimulation is not automatically beneficial. If very few small follicles remain after the first collection, waiting for the next cycle may be more productive. The decision depends on the ultrasound findings and the number of follicles available for a second round.
Follicles can be recruited in more than one wave during the cycle, making luteal phase start possible. Instead of beginning stimulation at the start of menstruation, medication begins during the second phase of the cycle.
Egg quality with luteal-phase stimulation has been shown to be equal or sometimes better, but the approach is more difficult to organize. Hormone levels need to be interpreted carefully, and an experienced team is required. It cannot be paired with a fresh transfer, so the embryos must be frozen.
This strategy may be useful when there is little time to wait, including for oncological patients who need fertility preservation. It may also be used as part of double stimulation. If follicle numbers appear better later in the cycle, beginning stimulation during that phase may be considered.
Some patients are offered treatments in addition to standard gonadotropins. Growth hormone is sometimes used with stimulation, particularly in poor ovarian reserve, with the proposed aim of improving egg maturity. It remains experimental and is not completely evidence-based.
Other adjuncts include DHEA, testosterone patches, hCG injections and letrozole. These are intended to increase androgen levels inside the follicles and potentially improve follicular recruitment. They are not first-line treatments and are generally considered when a previous protocol has not worked well.
Supplements such as coenzyme Q10, DHEA, myo-inositol, melatonin, vitamin D and omega-3 may also be discussed. Some are used mainly for poor ovarian responders and others for patients with polycystic ovaries. Patients considering these options should raise them before the cycle begins so the treatment team can decide whether they fit the overall plan.
A useful consultation should address more than the medication dose. Patients may want to ask:
These questions help clarify whether the plan is genuinely individualised. They also make clear which decisions are made before treatment and which depend on real-time monitoring.
Ovarian stimulation is a carefully adjusted process rather than a contest to obtain the highest possible dose or the greatest number of injections. The antagonist protocol is often a sensible starting point, but mild combination treatment, progesterone suppression, luteal-phase stimulation or double stimulation may be considered when the patient’s reserve, urgency or prior response calls for a different strategy.
The safest plan is one that changes when the follicles and blood tests provide new information. Trigger choice and the decision between fresh and frozen transfer should be guided by those results, not fixed in advance. For patients considering IVF, the central question is not “Which protocol is best?” but “Which protocol best matches my body and the goal of this cycle?”
There are two approaches to medication dosing. One approach is that the more eggs collected, the higher the chances, so when there are enough follicles to stimulate, higher doses are preferred.
The other approach is that very high doses of gonadotropins may overburn the follicles, increase oxidation inside the follicles, and reduce egg quality. However, this is not completely evidence-based.
In women with poor ovarian reserve who have only three or four follicles, high doses will not produce more eggs. In that situation, there is no reason to pay for more medication if the same number of eggs can be obtained with lower approaches. The dose strategy should reflect the number of follicles available and how the ovaries respond during stimulation.
The risk of ovarian hyperstimulation is higher in patients with polycystic ovaries, younger women, women with high AMH, thin women, and patients with good ovarian reserve.
Safety measures include using an agonist protocol, using agonist trigger injections, checking blood tests, adjusting doses when estrogen becomes very high, and freezing all embryos. At Bellarcos IVF, there has been 0 severe hyperstimulation in the last 4 years.
When a patient is expected to get only three or four eggs in one cycle, collecting more eggs can be helpful because more eggs increase the statistical chance of having a chromosomally normal embryo, especially in older age groups.
Embryo banking can be carried out over more than one cycle or through double stimulation. Double stimulation can collect more eggs in a shorter time during the same cycle, but it is not always worth doing. If there are not enough follicles after the first egg collection, it may be better to wait for the next period rather than proceed immediately.
The treatment plan can change significantly after stimulation has begun. The follicles and blood tests guide the process, so the team should monitor frequently and adjust the doses according to the results.
If estrogen levels become high, the dose may be reduced. If LH levels drop, a medication containing LH may be added. If an antagonist lowers LH too much and immature eggs may result, the antagonist can be stopped. This is the essence of personalisation: the medication plan is adjusted according to the patient’s response rather than followed rigidly.
No. A heterotopic pregnancy means that there is a pregnancy both inside and outside the woman’s uterus. The incidence should be about 1%.
Mini IVF usually means milder IVF. The usual doses of gonadotropins such as Gonal-f or Pergoviris are 150, and sometimes 225.
The exact dose should still be decided according to the woman’s age, the number of follicles, her AMH, and other factors. These details determine whether a milder stimulation approach is appropriate and which dose is used.
